1. Field
The invention is in the field of methods and apparatus for administering hyperthermia treatments and brachytherapy treatments.
2. State of the Art
As is generally known, heating to temperatures elevated above a normal cell temperature causes death or necrosis of living tissue. Further, the death rate of such heated tissue is a function of both the temperature to which it is heated and the duration for which the tissue is held at such temperatures.
It is also well known that the elevation of temperature of living tissue can be produced with electromagnetic energy at frequencies greater than about 10 kHz. Microwave frequencies that are above 300 MHz have generally been used for this purpose with a preference for 915 MHz, as approved by the Federal Communications Commission for medical devices.
It has been reported that some types of malignant cells may be necrotized by heating them to a temperature which is slightly below the temperature injurious to most normal cells. In addition, some types of malignant cells may be selectively heated and necrosed by hyperthermia or thermal therapy techniques because masses of these malignant cells typically have considerably poorer blood flow and thus poorer heat dissipation properties than does the surrounding normal tissue. As a result, when normal tissue containing such malignant masses is heated by EMR (electromagnetic radiation), the resultant temperature of the malignant mass may be substantially above that of the surrounding healthy tissue.
It has been determined that most malignant cells have significant damage by heat alone when heated at temperatures over 43° C. for at least 30 minutes. It has also been shown that for every degree increase in temperature above 43° C., the effective thermal dose and tissue damage is doubled. Thus, the same thermal dose would be expected at temperatures of 43° C., 44° C., and 45° C. for respective treatment times of 60, 30, and 15 minutes.
It has also been shown that the combined use of radiation therapy with higher temperatures greatly increases the damage to cells. This increased cell damage is decreased as the heating treatment and the radiation treatment are separated in time. It has been shown by Overgaard that the tissue damage to cancerous tumors is boosted by a factor of 2.5 for a standard radiation dose by adding hyperthermia at the same time.
For over 25 years, hyperthermia and radiation have been studied both clinically and in animal tumor models. Everyone has recognized that there is a benefit for combining hyperthermia and radiation, but the problem has always been how one could best do it. Biological and animal studies continually confirm that simultaneous treatment with the two methods would produce greater cell kill and damage to the tumor. However, the devices and methods of these two modalities were not very compatible for simultaneous treatments. Also, the exposure of normal tissues to the same combined doses increased the damage to the normal tissue. Over the years nearly all the clinical studies of radiation plus hyperthermia were conducted using standard radiation therapy scheduling where about 2 Gy of radiation was applied 5 times per week for about 6 weeks for a total dose of 60 Gy. This is generally considered a rather high dose for external beam radiation. Yet, it was common for hyperthermia to only be applied once or twice per week. This was largely because of biological concerns that thermal tolerance would develop in the tissues making the tumor less damaged by the same hyperthermia treatment if it was not separated by at least 48 hours from the previous hyperthermia treatment. Also it was common for the radiation therapy to proceed hyperthermia due to scheduling problems in radiation departments. There was usually about 30 to 60 minutes from the radiation treatment until the patient was actually at therapeutic temperatures. The fact that normally only about ⅕th of the radiation treatments had a concomitant hyperthermia treatment meant that a rather small portion of these radiation treatments would have any resulting enhancement of the tumor damage. There was also direct tumor damage from the heat itself that would typically cause rapid initial reduction of the tumor.
Overgaard Studies
Much of the early pioneering basis for this combination originated from the research of Overgaard. In 1980, Overgaard published a study using nude mice to determine the affects of hyperthermia and radiation time sequencing with various temperatures and treatment times. (Overgaard, Simultaneous and Sequential Hyperthermia and Radiation Treatment of an Experimental Tumor and Its Surrounding Normal Tissue in Vivo, 1980, Int. J. Radiation. Onc. Biol. Phys., Vol 6, pp. 1507-1517). In this work, Overgaard used a new term called the Thermal Enhancement Ratio (TER). This is defined as the radiation dose that is required to obtain a given end point with radiation alone relative to the radiation dose needed for the same effect with combined heat and radiation. Evaluation of the TER was primarily based upon the radiation dose which indicates local control at 120 days after treatment in 50% of the animals. When the presence of the tumor was not detectable, they used histopathological studies to determine the performance. In this study, the basis of thermal dose was established. At the time, they were trying to determine if scheduling of the radiation and hyperthermia treatment might be able to increase the effect on the tumor more than the affect to normal tissue exposed to the same treatment doses. This study did not show much of a difference between normal and tumor damage. However, it did show that there were significant benefits to combining the radiation and the hyperthermia at the same time if the application of the dose could be avoided on normal tissues.
Overgaard showed that one hour of heating at 43.5° C., could increase the TER to 4.9 for a 60 minute heating, 2.54 for a 30 minute heating, and 2.37 for a 15 minute heating. This means that at 43.5° C. for 15 minutes delivered simultaneously with a radiation dose of 30 GY would be equivalent to a radiation dose of 71 Gy. Yet, the long term affects of radiation would be predicted to only be that of the 30 Gy. A factor of over 2 is a tremendously powerful enhancement to boost effectiveness and potentially treatment durability.
The Overgaard mouse studies also show that when the hyperthermia was 24 hours before or after the radiation treatment the TER was 1.5. This implies that there was additional benefit even when there was a 24-hour time separation between hyperthermia and radiation. This should be also taken into account when evaluating the enhancement affects.
In this work, it was also shown that for a heat treatment to follow a radiation treatment by about 60 minutes, the TER would drop to 2.06, which is 86% of the value for simultaneous treatment.
Review of Stone and Dewey Studies in Vitro CHO Cells
The published in vitro studies by Dewey, (Stone and Dewey, Biologic Basis and Clinical Potential of Local-Regional Hyperthermia, Radiation Oncology, Vol. 2, Editor Phillips and Wara, 1987 Raven Press, NY., pg. 1-33), showed that heat to 42.5° C. for 60 minutes when combined with a single radiation treatment of 5 Gy produced a cell survival of only about 1.4×10−4 for cells with a pH of 6.7. This effect was observed even when hyperthermia was applied for up to 180 minutes before radiation. This same benefit was not seen for cells with pH of 7.45 when significant time separated the hyperthermia and the radiation treatment. However, when the hyperthermia and radiation were simultaneous, the survival of the high pH cells (2×10−4) almost reached that of the low pH cells. When there was a 60-minute separation between the hyperthermia and radiation the survival of the high pH cells increased to about 1.5×10−3. So about 10 times more of the high pH cells survived with a 60-minute separation as compared with simultaneous treatments. This demonstrates the significant benefit of simultaneous use of hyperthermia and radiation.
In vivo studies of Dewey showed that by heating to 42.5° C. for 60 minutes, when combined with simultaneous radiation, the TER reached 2.5. This changed to about 1.5 to 1.8 when there was a 60 minutes separation between the two treatment modes.
Review of Steeves Brachytherapy and Hyperthermia
Steeves et al. published results of the timing sequencing of hyperthermia and brachytherapy on intraocular tumors in 45 rabbit eye melanomas. (Steeves et.al. Thermoradiotherapy of Intraocular Tumors in an Animal Model: Concurrent vs. Sequential Brachytherapy and Ferromagnetic Hyperthermia, 1995, Int. J. of Radiation Oncology, Biology, Physics, Vol. 33 (3), pp. 659-662.). The study uses a single radiation and hyperthermia treatment. The plague-scleral interface was heated to 46-47° C. for one hour. Treatments with simultaneous heating and radiation were compared to these when hyperthermia was given 1 hour after radiation. With a follow-up of 4 to 10 weeks, they found that simultaneous hyperthermia and radiation therapy produced a 4.4 thermal enhancement ratio as compared to only a 1.4 value for the sequential treatments.
Review of Hyperthermia Plus Radiation Clinical Practices
There have been many Phase I, II, and III clinical studies that have been reported in the literature that combined radiation with hyperthermia. These studies almost always concluded that significant benefits resulted from the combination for both short and long term. All of these studies have been performed using between 3 and 10 hyperthermia treatments combined with typically 25 to 30 external beam radiation treatments.
Dr. Penny Sneed's study on Glioblastoma (Sneed, et al., Survival Benefit of Hyperthermia in a Prospective Randomized Trial of Brachytherapy Boost ±Hyperthermia for Glioblastoma Multiforme, 1998, Int. J. of Radiation Oncology, Biology, Physics, Vol. 40 (2), pp. 287-295) applied brachytherapy for 5 days, with hyperthermia for 30 minutes prior to and after the brachytherapy. At the rate of between 0.4 to 0.6 Gy/hr, most of the radiation dose would not be significantly enhanced by the hyperthermia as a result of hyperthermic radiosensitization. However, there may have been additional benefits from reoxygenation.
Expectations for Past Studies from Literature
A conclusion that can be drawn is that relatively few radiation treatments performed with hyperthermia treatment were enhanced by the addition of hyperthermia because most of the radiation was not performed in close time relationship with the hyperthermia. On average, it is estimated that about 5 hyperthermia treatments would be used over a typical radiation treatment regime of about 30 treatments in about 6 weeks. This means that only ⅕th of the radiation treatments were significantly complimented by the hyperthermia.
Implications for Brachytherapy Plus MW Interstitial Hyperthermia
The possibility exists to provide simultaneous treatment with hyperthermia and radiation when high dose rate (HDR) is used and common treatment delivery devices are used. Such has motivated the work of Martinez. If each of the brachytherapy treatments using HDR were combined with simultaneous hyperthermia and if the hyperthermia treatment was to raise 50% of the tumor volume to a temperature over 43.5° C. for 30 or 60 minutes, the predicted TER from Overgaard would be between 2.5 to 5. However, a time delay of about 15 minutes between the hyperthermia and the radiation would drop this by a factor of 0.92. The results for a 50 Gy plus hyperthermia treatment would then be equivalent to a radiation dose of 115 to 230 Gy. This higher dose effect would clearly be in the portions of the tumor that more easily would reach the temperature of 43.5° C. or above. This would be the necrotic region with lower blood flow that tend to be significantly radiation resistant. Current experience has led to the understanding that the addition of hyperthermia to standard radiation therapy does not increase short term or long-term toxicity or morbidity. There has however been an increased incidence of superficial blisters or burns of about 3 to 5%. It should be noted that for superficial hyperthermia treatment temperatures within 50% of the tumor would generally not exceed 42° C. due to patient discomfort or pain. Interstitial treatments generally are not as limited by patient pain since the energy is delivered more directly within the tumor. In the Sneed study, analysis of temperatures showed that 50% of the tumor had an equivalent treatment of 43° C. for a total of 75 minutes, while normal tissue temperatures were not allowed to exceed 44° C. The tumor was not allowed to exceed 50° C. This showed the clinical feasibility of utilizing MW Interstitial treatments to reach temperatures of 43 to 43.5° C.
Discussion
Since such impressive results have been observed with the combination of hyperthermia and radiation even when only a small number of radiation treatments are combined with the heat, it is clear that if simultaneous or near simultaneous treatments are delivered with MW Interstitial treatment where the local tumor temperatures can reach a higher level and most of the radiation dose can be significantly enhanced by the hyperthermia there could be significant future benefits. The MW Interstitial combination with HDR appears to offer a boost of between 2 to 5 depending on how it is implemented with the HDR and the duration of heating between 30 to 60 minutes. Such a significant enhancement represents major end results for response durability, radiation dose reduction, treatment efficiency, reduction or elimination of external beam treatment (in some cases) and reduction of patient toxicity.
Overgaard summarized in a published article in 1992 regarding the Future of Hyperthermia Oncology (Overgaard, The Future of Hyperthermic Oncology, Proceedings of the 6th International Congress on Hyperthermia Oncology, Volume 2, 1992, pp. 87-92) the following:                So far most of the results of the combined treatment have utilized the cytotoxic effect of hyperthermia which results in a heat-destruction of radioresistant (hypoxic) tumor cells in solid tumors. In addition to that we have the radiosensitizing effect, which yields a very prominent (temperature and treatment time dependent) enhancement of the radiation damage in normal tissues and tumors. . . . Until now, we have assumed that the therapeutic limitation is the normal tissue tolerance and that a selective heating or radiation treatment of a tumor without involving the surrounding normal tissue will be too heavy a task if the modalities should be applied simultaneously. This concept should be reevaluated since application of hyperthermia together with a boost of radiotherapy is likely to yield a very substantial enhancement, which may have significant implications for the tumor control probability. . . . If hyperthermia should have a meaningful place in curative radiotherapy, we should give maximum priority to further exploration of the hyperthermic radiosensitization and develop our heating techniques accordingly. Both technically, biologically, and clinically should this treatment principle be given the utmost priority in the future research.        
Overgaard further emphasized that Interstitial heating and radiation methods open the possibilities to accomplish this enhancement. If there is an hyperthermia enhancement of 2 a high dose 70 Gy radiation treatment could be reduced to 35 Gy for the same tumor result with much lower problems for the patient. The 35 Gy is in the range permitting recurrent radiation treatments after prior radiation failure, so it is also quite suitable for recurrent disease as well as primary.
The facts strongly supporting a simultaneous or close time relationship between radiation therapy and hyperthermia for maximizing the thermal enhancement ratio between radiation and hyperthermia indicate the need for a device to enable a shorter time between radiation and hyperthermia and the possibility of simultaneous treatments.